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.

Obesity-induced chronic inflammation plays a key role in the pathogenesis of insulin resistance and the metabolic syndrome. Proinflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signaling transduction. Interleukin-1 receptor-associated kinase-1 (IRAK-1) is a serine/threonine kinase functioning in Toll-like Receptor signaling pathways, and plays an important role in inflammation and immune response. In our studies, we demonstrated that IRAK-1 is involved with the negative regulation of PI3K-Akt dependent signaling pathway induced by insulin and TLR 2&4 agonists. Out data also indicate that IRAK-1 can interact with IRS-1 protein both in vivo and in vitro. The binding sites for the IRAK1-IRS1 biochemical interaction are IRS-1's PH domain and IRAK-1's proline-rich LWPPPP motif. Our studies also indicate that IRAK-1 is involved with the negative regulation of glycogen synthesis through inhibiting PI3K-Akt signaling pathway and thus releasing GSK3β's inhibitory effect on glycogen synthase. Moreover, our studies also suggest that IRAK-1 is involved in the activation of transcription factors CREB and ATF-1 by stimulating CREB-Ser133 and ATF-1 phosphorylation. CREB transcription factor family induces genes involved in cellular metabolism, gene transcription, cell cycle regulation, cell survival, as well as growth factor and cytokine genes. That may partially explain our finding that IRAK-1 may be also involved with cell proliferation and survival pathway. / Master of Science