abstract: Cardiovascular disease and diabetes are major health burdens. Diabetes is a primary risk factor of cardiovascular disease, and there is a strong link between obesity and risk of developing diabetes. With the prevalence of prediabetes highest among overweight/obese individuals, investigation into preventative strategies are needed. Aerobic exercise is a potent stimulus for both insulin and non-insulin dependent glucose uptake into the skeletal muscle. A single exercise session can improve insulin sensitivity within hours after exercise. The effects of intensity, type, and volume of exercise on glucose homeostasis have been studied extensively; however, controlling for muscle contraction frequency with a constant exercise intensity and workload has not been examined. The purpose of this study was to compare muscle contraction frequency during aerobic exercise by altering cycling cadence on insulin sensitivity and vascular health. Eleven obese males (age=28yr, BMI=35kg/m2) completed three conditions in random order: 1) control-no exercise; 2) 45-min cycling at 45 revolutions per minute (45RPM) at 65-75%VO2max; 3) 45-min cycling at 90RPM at 65-75%VO2max. Glucose control and insulin sensitivity were assessed with oral glucose tolerance tests (OGTT) 4 hours post-exercise. Vascular health was assessed via flow-mediated dilation (FMD) pre-exercise, 1-hr and 2-hr post exercise and ambulatory blood pressure was assessed pre-exercise, and continually every 15 min post-exercise. Linear mixed models were used to compare the mean differences in outcome variables. There were no significant differences found between control and both exercise conditions for all OGTT outcomes and no differences were found between control and exercise in FMD (all, p>0.05). Significant effects for exercise were found for both brachial and central blood pressure measures. Brachial systolic blood pressures were lower at 2- and 4-hr post-exercise by approximately -10 and -8mmHg, respectively (p<0.001 and p=0.004) versus control. Central systolic blood pressures were lower at 2-, 3-, and 4-hr post-exercise by approximately -8, -9 and -6mmHg, respectively (p<0.001, p=0.021 and p=0.004) versus control. In conclusion, aerobic exercise, regardless of muscle contraction frequency, were unable to effect glucose control and insulin sensitivity. Similarly, there was no effect on vascular function. However, there was a significant effect of aerobic exercise on reducing post-exercise blood pressure. / Dissertation/Thesis / Doctoral Dissertation Exercise and Nutritional Sciences 2017

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第22779号 / 工博第4778号 / 新制||工||1747(附属図書館) / 京都大学大学院工学研究科電気工学専攻 / (主査)教授 土居 伸二, 教授 萩原 朋道, 教授 小林 哲生, 教授 古谷 栄光 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Vaspin expression is increased in white adipose tissue (WAT) of diet-induced obese mice and rats and is supposed to compensate HFD-induced inflammatory processes and insulin resistance in adipose tissue by counteracting pro-inflammatory gene expression in obesity. Multiple studies have also demonstrated strong anti-inflammatory effects in vascular and skin cells. Here, we used vaspin treated 3T3-L1 murine adipocytes as well as 3T3-L1 cells with stable vaspin expression to investigate the effect of exogenous and endogenous vaspin on inflammatory processes and insulin signaling in adipocytes. Our stably transfected cells secreted significant amounts of vaspin which was in the physiological range of ∼0.5 ng/ml in cell supernatants. Adipocyte differentiation was not affected by vaspin as expression of adipogenic marker genes as well as lipid accumulation after full differentiation was similar to control cells. We found that IL-1β induced expression and secretion of pro-inflammatory cytokines, such as IL-6, MCP1 and TNFα was significantly blunted in vaspin expressing 3T3-L1 cells. Treatment of 3T3-L1 cells with exogenous vaspin resulted in reduced cytokine-induced activation of the intracellular and pro-inflammatory NFκB signaling cascades (IKKα/β, IκB and NFκB). Moreover, endogenous vaspin positively affected insulin signaling by increasing insulin-stimulated phosphorylation of the key mediator protein kinase B (AKT). Together, we demonstrate anti-inflammatory effects of vaspin in 3T3-L1 adipocytes as well as increased insulin signaling by endogenous expression or exogenous treatment. The results provide evidence for potent anti-inflammatory action of vaspin not only in vascular cells but also in adipose tissue.

Indiana University-Purdue University Indianapolis (IUPUI) / Because colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer death in the US, identifying biomarkers that might inform disease prevention and early diagnosis is of great public health importance. Mitochondria are key cytoplasmic organelles containing an independent genome, i.e., mitochondrial DNA (mtDNA). It has been increasingly recognized that mtDNA copy number (mtDNAcn) is a biomarker for mitochondrial function and cellular oxidative stress. To date, the few studies that have assessed associations between mtDNAcn and CRC outcomes have yielded inconsistent findings. Further, no epidemiologic study has examined the relationship between insulinemic potential of lifestyle and mtDNAcn. Therefore, in this dissertation, three studies were conducted using data from the Nurses’ Health Study and the Health Professionals Follow-Up Study. First, the association between pre-diagnostic leukocyte mtDNAcn and CRC risk was studied in a nested casecontrol study (324 cases/658 controls). Lower mtDNAcn was significantly associated with increased risk of CRC and proximal colon cancer. That inverse association remained significant among individuals with ≥ 8 years’ follow-up since blood collection, suggesting that mtDNAcn might serve as a long-term predictor of CRC risk. Second, possible associations of pre-diagnostic mtDNAcn with overall and CRC-specific survival were examined among 587 CRC patients. MtDNAcn was not significantly associated with survival overall or in subgroups by cancer location, grade, or stage. Among current smokers, there was an inverse association between one standard deviation (SD) decrease in mtDNAcn and increased overall death risk. Among patients diagnosed at or before 70.5 years of age and those with anti-inflammatory diets, reduced mtDNAcn was associated with lower CRC-specific death risk. Lastly, the cross-sectional association between empirical lifestyle index for hyperinsulinemia (ELIH) and mtDNAcn was investigated among 2,835 subjects without major chronic diseases (cancers, diabetes, and cardiovascular diseases). A significant inverse association was found: least-squares means ± SD of mtDNAcn z-score decreased dramatically across ELIH quintiles. Overall, the findings from this dissertation will contribute to the evaluation of mtDNAcn as a potential biomarker for CRC risk and prognosis, and inform future interventions designed to reduce the insulinemic potential of lifestyle factors to preserve mitochondrial function. / 2022-04-06

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19171号 / 医博第4013号 / 新制||医||1010(附属図書館) / 32163 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 柳田 素子, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Background: This study was conducted to determine the association between fiber intake and insulin resistance in 264 women using a cross-sectional design. Methods: Insulin resistance was indexed using HOMA-IR (fasting insulin (μU/mL)×fasting glucose (mg/dL)/405). HOMA-IR values were log transformed. Fiber and energy consumption were assessed using 7-day weighed food records. Fiber was expressed as grams per 1000 kilocalories. Body fat percentage (BF%) was measured using the BOD POD and physical activity (PA) was ascertained using Actigraph accelerometers worn for 7 consecutive days. Results: (Mean±SD) age: 40.1±3.0 years, glucose: 86.7±5.9 mg/dL; insulin: 7.1±4.3 μU/mL; HOMA-IR: 1.5±1.0; fiber intake (g/1000 kcal), total: 9.3±2.9; soluble: 1.7±0.9; insoluble: 3.8±1.9; physical activity: 2.7044 ±0.7842 million counts; BF%: 31.7±6.9; weight (kg): 66.1±10.1; total caloric intake per day (kcal): 2054.1±320.9; and dietary fat intake (% of total kcal): 30.5±0.5. Women with high total fiber intakes had significantly less insulin resistance than their counterparts (F=4.58, p=0.0332), and women with high soluble fiber intakes had significantly lower levels of insulin resistance than other women (F=7.97, p=0.0051). Participants with high insoluble fiber intakes did not differ from their counterparts (F=0.7, p=0.6875). Adjusting for either PA or BF% weakened the relationships significantly. Controlling for BF% nullified the total fiber-HOMA-IR link (F=1.96, p=0.1631), and attenuated the association between soluble fiber and HOMA-IR by 32% (F = 6.86, p=0.0094). To facilitate interpretation of the results, odds ratios were calculated to determine the association between fiber intake and HOMA-IR with both variables treated as categorical. To create dichotomous variables, fiber intake and HOMA-IR were each divided into two categories using the median (Low and High). In women who had high soluble fiber intake (upper 50%), the odds of having an elevated HOMA-IR level was 0.58 (95% CI: 0.36-0.94) times that of women with low soluble fiber intake (lower 50%). And after controlling for all of the potential confounding factors simultaneously, the odds ratio was 0.52 (95% CI: 0.29-0.93). Conclusion: High fiber intake, particularly soluble fiber, is strongly related to lower levels of insulin resistance in women. Part of this association is a function of differences in PA and BF%.

This thesis sought to advance our understanding of the physiological and health-related adaptations to low-volume interval training. Three separate studies were conducted in previously sedentary adults who trained three times per week. High-intensity interval training (HIIT) involved ten, 60-second cycling efforts at an intensity that elicited ~90% of maximal heart rate, interspersed with 60 seconds of recovery, whereas sprint interval training (SIT) involved three, 20-second ‘all-out’ cycling efforts interspersed with 2 minutes of recovery. Both protocols involved a brief warm-up and cool-down, resulting in 25- and 10-minute sessions for HIIT and SIT, respectively. Peak oxygen uptake (VO2peak), skeletal muscle mitochondrial content as reflected by the maximal activity and protein content of mitochondrial enzymes, and glycemic control based on oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs) or continuous glucose monitoring (CGM), were determined before and after training. Study 1 found that 6 weeks of HIIT in the fed or fasted state increased VO2peak and mitochondrial content in women, but insulin sensitivity based on OGTTs was unchanged. Study 2 showed that 6 weeks of SIT increased VO2peak and mitochondrial content in men and women, whereas mean 24-hour glucose based on CGM was reduced in men only. Study 3 directly compared 12 weeks of SIT to traditional moderate-intensity continuous training (MICT) in men. The two protocols elicited similar improvements in VO2peak, mitochondrial content and insulin sensitivity based on IVGTTs, despite SIT involving a five-fold lower exercise volume and time commitment. This work advances our understanding of the potency of brief, intense exercise training to induce physiological remodeling and improve cardiometabolic health. It also highlights potential sex-specific adaptations to interval training that warrant clarification. Further investigation into the mechanisms of physiological remodeling to HIIT and SIT is needed, as are large-scale randomized clinical trials that compare these protocols to MICT. / Thesis / Doctor of Philosophy (PhD) / This thesis examined physiological and health-related adaptations to interval training, which involves brief bouts of intense exercise interspersed with recovery periods. One protocol involved alternating 60-second hard and easy cycling efforts for 20 minutes; the other involved three, 20-second ‘all-out’ sprints interspersed with 2 minutes of recovery. Both protocols improved indices of cardiometabolic health in previously inactive adults who trained three times per week for 6 weeks, even though the amount of exercise performed was lower than typically recommended in public health guidelines. When the latter protocol was directly compared against traditional endurance training, the improvement in cardiometabolic health after 12 weeks was the same, despite a five-fold difference in the total amount of exercise performed. Our findings highlight the effectiveness of short bursts of high-intensity exercise for improving health. These results may appeal to individuals who cite “lack of time” as a barrier to exercise.

Polycystic ovary syndrome (PCOS) affects a substantial percentage of reproductive-aged females. Diagnosis criteria include irregular ovulation, elevated androgens, and polycystic ovaries. PCOS often presents with metabolic and reproductive symptoms, with insulin resistance being a symptom that exacerbates metabolic issues. Exercise as a non-pharmacological intervention is featured in the literature on management of PCOS. The objective of this thesis is to explore the role of exercising in mitigating insulin resistance in women with PCOS. A search for relevant articles that included different exercise methods such as high intensity training was completed using CINAHL and Medline. High intensity training appears to have a more comprehensive effect on metabolic levels, though other exercises offer benefits. Further research should include large and diverse sample sizes, longer research duration, and focus on defining an optimal exercise guideline for women with PCOS.