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肥胖發炎與糖尿病. 國防醫學院生理學研究所 謝 博軒教授兼所長. 成人肥胖定義及分類. 定義 肥胖是指體脂肪囤積過多 評估方式 身體質量指數 (body mass index, BMI) = Body weight (kg) / height 2 (m 2 ) 與體脂肪有高度相關性 BMI 易造成分類錯誤之個案 , 運動員 ( 高估 ) 、 少女和年長者 ( 低估 ) 合併腰圍和 BMI 測量 , 能減少錯誤分類 相同 BMI ≠ 相同體脂率 ( 男 < 女 , 年長 > 年輕 ). “Thrifty gene” hypothesis.

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slide1

肥胖發炎與糖尿病

國防醫學院生理學研究所

謝博軒教授兼所長

slide2
成人肥胖定義及分類
  • 定義 肥胖是指體脂肪囤積過多
  • 評估方式
    • 身體質量指數 (body mass index, BMI) = Body weight (kg) / height2 (m2) 與體脂肪有高度相關性
    • BMI 易造成分類錯誤之個案,運動員(高估) 、 少女和年長者(低估)
    • 合併腰圍和 BMI 測量,能減少錯誤分類
    • 相同BMI ≠ 相同體脂率(男<女,年長>年輕)
slide5

台灣成人過重與肥胖的盛行率

The prevalence of overweight (BMI>24 kg.m-2) and obesity

(BMI>27 kg.m-2) in Taiwanese adults categorized by gender

and calendar years (Obesity review 2008)

slide16

肥胖組織發炎與胰島素抗性

Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance

J Clin Invest. 112(12):1821-30 (2003).

Obesity is associated with macrophage accumulation in adipose tissue J. Clin. Invest. 112:1796–1808 (2003).

Crown-like structure

slide19

Adaptive immune system

Arterioscler Thromb Vasc Biol.

2008;28:1211-1213

slide20

T-cell and RANTES

Circulation. 2007;115:1029-1038

International Journal of Obesity (2008) 32, 451–463

slide21

後天免疫系統對脂肪組織發炎的影響

15 (8): 914-921, 2009

15 (8): 930-939, 2009

slide22

Adipose tissue cell interactions during High-fat diet induced

inflammation

CIITA, class II transactivator, the master transcriptional regulator of the MHCII pathway

MHCII, major histocompatibility complex II

Cell Metabolism 17:411-422, 2013

slide24
肥胖造成發炎反應機轉及系統性胰島素抗性產生關係肥胖造成發炎反應機轉及系統性胰島素抗性產生關係
slide27
抗發炎性藥物在肥胖誘發胰島素抗性和心血管疾病的治療潛力抗發炎性藥物在肥胖誘發胰島素抗性和心血管疾病的治療潛力

■ Yuan MS et al. Reversal of obesity- and diet-induced insulin resistance

with salicylates or targeted disruption of IKKβ.

Science 2001 31:1673-1677

slide30

■Hirosumi J et al. A central role for JNK in obesity and insulin resistance.

Nature 2002 420:333-337

JNK, c-jun amino-terminal kinase

slide32

The Importance of Adipose Cyclooxygenase 2 activation in the Development of

Obesity-induced Insulin Resistance and Fatty Liver

Circulation 2004;109;1729-1734

slide33

COX 2 Activation and Obesity-induced adipose inflammation

Obesity

COX-2 inhibitor

COX-2 ↑

MCP-1↑

MCP-1↓

TNF-α、MCP-1

Improved insulin sensitivity

slide34

COX 2 Activation and Obesity-associated suppression

In adipocyte differentiation

Adipose tissue inflammation

Pro-inflamatory cytokines and chemokines

TNF-α, MCP-1

Adipocyte hypertrophy

COX-2 inhibitor

COX-2

COX-2

Differentiation

slide35

European Journal of Clinical Investigation 2008 38 (11): 812-819.

Obesity 2009 17(6):1150-1157

European J Clinical Investigation 2010:40(2):164-171

Life Science 2011:89:107-114

slide38

Nature Medince 15(8):921-930, 2009

Diet-induced obese mice

ob/ob obese mice

CD3-specific antibody 10 ug/d x 5

Lasting > 4 months

T helper type 1 (TH1) cells

T helper type 2 (TH2) cells

slide39
結論

肥胖發炎在第二型糖尿病的發展上扮演重要角色

肥胖發炎主要來自於脂肪組織發炎

先天(Innate immunity)和後天免疫(adaptive immunity)系統在肥胖造成脂肪組織發炎中均扮演重要角色

特定抗發炎性藥物具有改善肥胖發炎和胰島素抗性的潛力

免疫治療具治療肥胖相關第二型糖尿病的潛力

slide40
身體對營養過剩與病原體感染之反應系統之異同身體對營養過剩與病原體感染之反應系統之異同
slide42
肥胖治療策略

減重(飲食運動)

抗發炎性藥物??

脂肪組織無發炎

脂肪組織發炎

正常生理功能

系統性胰島素抗性

心血管疾病

(需積極治療族群)

where will we be tomorrow
展望未來Where will we be tomorrow?
  • 肥胖盛行率往後可能會持續升高
  • 學者依目前肥胖增加趨勢,預計到2030年每個人都會變成肥胖