京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13165号 / 論医博第2152号 / 新制||医||1029(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 篠原 隆司, 教授 宮本 享, 教授 近藤 玄 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Growing evidence suggests that adipokines may be therapeutic targets for cardiometabolic diseases such as type 2 diabetes mellitus (T2DM). C1q TNF Related Protein 3 (CTRP3) is a newly discovered adipokine which shares properties with adiponectin. The literature about the association between circulating levels of CTRP3 and T2DM has been conflicting. The present study reassessed the data on circulating CTRP3 levels in T2DM patients compared to controls through a systematic review and meta-analysis. A literature search was performed in Medline, Embase, Scopus, and Web of science to identify studies that measured circulating CTRP3 levels in T2DM patients and controls. The search identified 124 studies of which 59 were screened for title and abstract and 13 were subsequently screened at the full text stage and 12 studies included into the meta-analysis. Subgroup analyses, depending on the presence of T2DM complications, matching for BMI, age, and cut off value of fasting blood sugar and HOMA-IR, were performed. The results show that circulating CTRP3 levels are negatively associated with T2DM status (SMD: −0.837; 95% CI: (−1.656 to −0.017); p = 0.045). No publication bias was identified using the Begg's rank correlation and Egger's linear regression tests (P = 1 and P = 0.44, respectively). Meta-regression demonstrated significant association between CRTP3 levels with BMI (slope: 0.11; 95% CI: 0.04–0.19; p = 0.001) and sex (slope: −0.07; 95% CI: −0.12 to −0.01; p = 0.008). The present systematic review and meta-analysis evidences a negative association between circulating level of CTRP3 and T2DM status. BMI and sex may modify this association.

Short-term physical inactivity in older adults has been shown to cause muscular atrophy and impaired glycemic control, however, the ability to recover remains unknown. We aimed to determine the impact of step-reduction (SR) on older adults and if they could recover simply by returning to habitual activity. Ten older adults (6 men, 4 women, 69 ± 3 yr) completed 7d of normal baseline activity (BL), subsequently underwent SR by 86 ± 9% (8568 ± 3741 to 973 ± 76 steps/d; p<0.001) for 14d and then returned to 8383 ± 4513 steps/d for 14d (RC). During an oral glucose tolerance test (OGTT), SR resulted in elevated plasma glucose concentration ([G]) area under the curve (AUC; 325 ± 126 to 375 ± 137, p = 0.13), maximum [G] (10.2 ± 2.4 to 11.9 ± 1.7 mM, p = 0.027) and 2-hr [G] (7.9 ± 1.3 to 9.1 ± 1.1 mM, p = 0.085), while all [G] indices returned to BL after RC. However, Matsuda insulin sensitivity index was reduced (3.5 ± 0.3 to 2.7 ± 0.7, p < 0.001) and homeostatic model assessment of insulin resistance was elevated (2.8 ± 0.3 to 3.6 ± 0.7, p = 0.02) with SR, remaining different than BL after RC (p < 0.005). During free-living conditions, 3-hr post-prandial [G] (PPG) AUC and peak PPG increased following SR (p > 0.05), returning to BL with RC. Body composition and physical function remained unchanged with SR. These results show that periods of physical inactivity, characterized by reduced daily stepping, do not present detectable changes in body composition or physical function yet result in reduced glycemic control in older adults. While elevations in blood [G] are abolished with 14d of normal physical activity, our findings suggest that the SR-associated reductions in insulin sensitivity are not normalized as quickly. / Thesis / Master of Science in Kinesiology / Periods of physical inactivity such as hospitalizations decrease daily steps for older adults and this inactivity can cause losses of muscle, strength, and symptoms of diabetes. It was unknown if by simply returning to normal physical activity older persons could ‘reverse’ the consequences of step-reduction so we conducted a study involving two weeks of step-reduction and two weeks of recovery. While there was no change in strength or muscle mass, we found that when older adults reduced their daily steps to fewer than 1000/day, after two weeks they became ‘resistant’ to insulin, a hormone that helps control blood sugar and is connected to the development of type II diabetes. Although these older adults resumed normal step-count levels in the recovery phase, they did not recover their insulin sensitivity such that two weeks of normal daily activity was not sufficient to overcome the consequences of two weeks of inactivity.

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Currently, it is reported that ~65% and 34% of the U.S. population is overweight and obese, respectively. Obesity is a major risk factor for cardiovascular disease. Overweight and obese individuals are also at an increased risk of developing hypertension. Whole-body insulin sensitivity is reduced in obesity, resulting in insulin resistance and increased risk of type 2 diabetes. One possible mechanism contributing to insulin resistance in obesity hypertension is renin-angiotensin system (RAS) overactivation. The RAS exhibits vasocontricting and sodium-retaining properties, yet in vivo and in vitro animal experiments suggest impairment of whole-body insulin sensitivity with increased angiotensin II (Ang II) exposure. Furthermore, evidence from clinical studies indicates Ang II receptor blockers (ARBs) may reduce the incidence of new-onset diabetes compared to other antihypertensive agents in at-risk hypertensive patients. However, it is unclear if whole-body insulin sensitivity is improved with Ang II receptor blockade in humans. Thus, we tested the hypothesis that 8-week Ang II receptor blockade with olmesartan would improve whole-body insulin sensitivity in overweight and obese individuals with elevated blood pressure (BP). Olmesartan was selected for the present study because it is devoid of partial PPARγ agonist activity. To test our hypothesis, intravenous glucose tolerance tests were performed to measure insulin sensitivity before and after control and ARB treatment in a randomized crossover manner. Because skeletal muscle tissue accounts for ~75-90% of insulin-stimulated glucose uptake, a secondary exploratory aim was to examine skeletal muscle inflammatory and collagen response in relation to insulin sensitivity during ARB treatment. No baseline differences were observed between treatments (P>0.05). Both systolic (-11.7 mmHg; P=0.008) and diastolic (-12.1 mmHg; P=0.000) BP were reduced with ARB treatment. Insulin sensitivity was not different between treatments (P>0.05). No correlates of insulin sensitivity were identified. In addition, skeletal muscle inflammatory and collagen gene expression did not change from pre- to post-ARB treatment (P>0.05). Our findings suggest that short-term RAS blockade in overweight and obese adults with elevated BP does not improve whole-body insulin sensitivity, despite a significant BP reduction. Further studies are needed to clarify the role of individual RAS blockers on insulin sensitivity during RAS inhibition in obesity hypertension. / Ph. D.

Diabetes mellitus is a major public health concern. Although the accessible novel drugs, techniques, and surgical intervention has improved the survival rate of individuals with diabetes, the prevalence of diabetes is still rising. Type 2 diabetes (T2D) is a result of chronic insulin resistance (IR) and loss of &beta;-cell mass and function. Therefore, the search for naturally occurring, low-cost, and safe compounds that could enhance insulin sensitivity and protect functional &beta;-cell mass can be an effective strategy to prevent this disease. Kaempferol, a flavonol present in various medicinal herbs and edible plants, has been shown to elicit various pharmacological activities in preclinical studies. However, studies investigating the effect of kaempferol on diabetes are limited. In this dissertation, I explored the anti-diabetic potential of dietary intake of kaempferol in diet-induced obese mice and insulin-deficient diabetic mice. First, kaempferol was supplemented in the diet to determine whether it can prevent IR and hyperglycemia in high fat (HF) diet-induced obese mice or STZ-induced obese diabetic mice. To evaluate its efficacy for treating diabetes, kaempferol was administrated once daily via oral gavage to diet-induced obese and insulin-resistant mice or lean STZ-induced diabetic mice. The results demonstrated that long-term oral administration of kaempferol prevents HFD-induced metabolic disorders in middle-aged obese mice. Oral administration of kaempferol improved glucose intolerance and insulin sensitivity, and this effect was associated with increased Glut4 and AMPKa expression in muscle and adipose tissues. Consistent with our findings from the in iii vitro study in C2C12 muscle cell line, these findings suggest that kaempferol may reduce IR at the molecular level by improving glucose metabolism in peripheral tissues. In the second study, dietary kaempferol supplementation prevented hyperglycemia and glucose intolerance by protecting &beta;-cell against the induced damage in obese STZ-induced diabetic mice. In the third study, the administration of kaempferol by oral gavage significantly ameliorated hyperglycemia and glucose intolerance and reduced the incidence of diabetes from 100 % to 77.8% in lean STZinduced diabetic mice. This kaempferol effect was associated with reduced hepatic glucose production, the primary contributor to hyperglycemia, and increased glucose oxidation in the muscle of diabetic mice. Kaempferol treatment restored hexokinase activity in the liver and skeletal muscle and reduced pyruvate carboxylase (PC) activity and glycogenolysis in the liver. Unlike its effect on T2D mice, kaempferol effect in lean STZ-induced diabetic mice was not associated with changes in plasma insulin levels. In the last study, we found that administration of kaempferol by oral gavage significantly improved blood glucose control by suppressing hepatic glucose production and improving glucose intolerance in obese insulin-resistant mice. Similar to its effect in old obese mice, kaempferol enhanced whole-body insulin sensitivity. Kaempferol increased Akt and hexokinase activity and decreased PC activity in the liver. However, kaempferol did not exert any changes in glucose metabolism or insulin sensitivity when administered to healthy lean mice. Overall, findings from these studies provide new insight into the role of kaempferol in the regulation of glucose homeostasis and suggest that kaempferol may be a naturally occurring anti-diabetic compound by improving insulin sensitivity, improving glucose regulation and metabolism, and preserving functional &beta;-cell mass. / Ph. D.