Chemistry of Medicine I (by Mori)

医用化学第一（森 担当分 4回）
Content:
0. Evolutionary Medicine 進化医学

1. Diabetic mellitus 糖尿病
2. Atherosclerosis 動脈硬化
3. Alzheimer’s disease アルツハイマー病
1 Download the handout from Katayama lab HP
リンク⇒講義資料

 Submit mini-test via e-mail to me.
mori.takeshi.880@m.kyushu-u.ac.jp
subject: mini-test

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Evolutionary medicine
進化医学

Molecular evolution
分子進化

Chemical evolution
化学進化

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Why we’d better think based on evolution?
なぜ進化で考えると良いのか？
Life is designed rationally to survive.
生命は生き残るために、合理的に設計されている。

Life is complicated. But evolution explains essenceof life.
枝葉に振り回されず、核心を知ることができる。

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0. Darwinian medicine (evolutionary medicine)
ダーウイン医学（進化医学）
 How people get sick => Why people get sick
 Why evolution has shaped these mechanisms

in ways that may leave us susceptible todisease.
 It works well to explain diseases including

1962
James Neelcancer, infection, autoimmunity, anatomy,
mental illness (がん、感染症、自己免疫疾患、解剖学、精神疾患）
5How to make question based on Darwinianmedicine
Q1: Why scurvy occurs?

壊血病という病気はなぜ起こるのか？
A1: Lack of vitamin C causes scurvy
Vitamin Cが欠乏すると壊血病になる。
Q2: Why lack of vitamin C causes scurvy?
vitamin Cが欠乏するとなぜ壊血病になるのか？
A2: vitamin C is needed for blood coagulation.
血液凝固にvitamin Cが必要だから
Q3: Why human does not biosynthesize important vitamin C? (Darwinian)

なぜ大事なvitamin Cを生合成しないのか？
A3: Up to rodent synthesize vitamin C. Change in metabolism and food.
げっ歯類までは生合成する。代謝系における変化。食物の変化。
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References

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Cause of death in Japan

Death ratio (per 105 people)

Cancer悪性新生物（がん）Cerebral infarction
脳血管疾患（脳卒中etc）

Heart disease
心疾患（心筋梗塞etc）
Pneumonia 肺炎
Accidental death
不慮の事故
Suicide 自殺
Lever disease 肝疾患
Tuberculosis 結核

1947

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6575859505

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Natural selection (Darwin, 1858)

The giraffe ancestor who has longer neck (the fittest)
survived, and then long necks became common in
population.
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Change in life style
200k years ago(hunting, sampling)

10k years ago(farming)

presentgrain (carbohydrate)
Livestock (milk)satisfaction (fat, carbohydrate,salt), lack of exercise
work at midnight
longevity, stressful, hygiene,10reading

Much exercise
Efficient energy absorption
Miscellaneous food
Small groupMismatch diseases
Acid reflux 胃酸の逆流

Flat foot 偏平足

Acne にきび

Gout 痛風

Alzheimer's disease アルツハイマー病

Hemorrhoid 痔Apnea 無呼吸

Hypertension 高血圧

Asthma 喘息

Insomnia 不眠症

Athlete’s foot 水虫

Irritable bowel syndrome 過敏性腸症候群

Cancer がん

Lactose intolerance 乳糖不耐性

Carious tooth 虫歯

Low back pain 腰痛

Cirrhosis of the liver 肝硬変

Metabolic syndrome メタボリックシンドローム

Constipation 便秘

Multiple sclerosis 多発性硬化症

Coronary heart disease 冠状動脈性心疾患

Myopia 近視

Crohn’s disease クローン病

Osteoporosis 骨粗しょう症

Depression うつ病

Scurvy 壊血病

Diabetes type 2 ニ型糖尿病

Ref: “The story of the human body”

11Person who overcomes mismatch diseases will appear bygenetic mutation. Is this genotype spread in homo sapience?
今後、Mismatch diseasesを進化で克服した個人が出てきたとして、その子孫がやがて人類のマジョリティーを占めるようになるか？

NO. Because mismatch diseases usually appear after reproductive
age, such genotype does not spread.
生殖年齢を終えた後の疾患は子孫を残す確率に無関係。

We should live with diseases.
病気と付き合っていく方法を考えねばならない。
Modern therapy utilizes life system for therapy and diagnosis.
僕たちができるのは、生命の仕組みを少々拝借して、治療や診断を行うこと。
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1. Diabetic mellitus (DM) 糖尿病
1. What is DM 糖尿病とは
2. Glycation causes diabetic complications 合併症の原因は糖3. Why human chose glucose?

なぜ、それでもヒトはglucoseを選んだのか？
4. Mechanism to control BGL 血糖値の調節機構
5. Cause of DM 糖尿病の原因
6. Therapy of DM 糖尿病の治療

131.1 What is DM 糖尿病とは

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Which one does include more glucose?

Total amount of blood ５Ｌ

Coke 350 mＬ

1 g/L x 5 L = 5 g

110 g/L x 0.35 L = 39 g
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Diabetic complications 糖尿病合併症

How dose high BGL cause these diseases?

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Diabetes mellitus
 High glucose conc. in blood. (≥ 126 mg/dL, HbA1c ≥ 6.5%)

 Type I: destruction of pancreatic b cell, leading to depletion of insulin.
Then become high glucose conc. 膵臓β細胞が破壊され、インシュリンが枯渇し、その結果、高血糖になる。
 Type II: decrease in secretion of and response to insulin. 90% ofdiabetes patients.
 5% of the world’s adult population. 7.4 million in Japan.
 Causing diabetic complications （合併症）：diabetic neuropathy 糖尿病性神経障害

diabetic retinopathy 糖尿病性網膜症

Microvascular disease 微小血管障害diabetic nephropathy 糖尿病性腎症
myocardial infarction 心筋梗塞

peripheral vascular disease 末梢血管障害

Macrovascular disease 大血管障害
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Mechanism of diabetic retinopathy
1. Endothelial cell (血管内皮細胞) and basement membrane (基底膜) exposed to highblood glucose conc.
2. Glycation of endothelial
membrane protein and basement
membrane protein.
3. Thickening and weakening ofbasement membrane.
4. Loss of pericyte (周皮細胞)
5. Leakage of plasma ⇒ Retinal
edema （浮腫）、exudate （滲出）6. microaneurysm（微小動脈瘤）⇒
hemorrhage（出血）18Diabetic retinopathy 糖尿病性網膜症

黄斑視神経191.2 Glycation causes diabeticcomplications
合併症の原因は糖化

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AGE (advanced glycation end product) 終末糖化産物
 Obtained by glycation of protein (Mailard reaction)
 Inducing protein denaturation leading to diabetic complications~100%

0.001%

hours

days

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AGE (advanced glycation end product) 終末糖化産物

weeks, months, years (Mailard reaction)

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Mailard reaction product tastes “Koku” コク Mailard reaction product itself is not tasty (bitter).
 But mixed with other taste, make the taste deeper one because of thesimultaneous stimulation of different taste receptors.

23BGL is not constantAffected by meal taking and daily stress. How can we remove such
short-term effects?

Blood glucose level

diabetic patient

potential diabetics

healthy
3 AM

7 AMbreakfast

12 pmlunch

8 pmdinner

3 AM
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Monitoring BGL by using hemoglobin (Hb) Half-life of red blood cell (RBC) is 2 months.
 Easy to sample enough amount of Hbs (90wt% of RBC in dry weight).
 Blood glucose conc. of more than a months can be monitored by checking Hb’s
glycation incorporated in RBC.
 HbA1c (one of b chains’ N-terminus is glycated) is used. Content of HbA1c isanalyzed by liquid chromatography.
 Diabetes: HbA1c ≥ 6.5%

N-terminalVal10 uma chainb chain

Green: RBC’s GLUT125

1.3 Why human chose glucose?
なぜ、それでもヒトはglucoseを選んだのか？

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Why do we choose troublesome glucose as energy source?
なぜ厄介なグルコースを栄養に選んだのか？

• Ｃ６の糖の中で、もっとも安全ではある。
The most stable C6 saccharide.
• エステルのように、加水分解しても酸が生じない。
Hydrolysis of glucose polymer does not generate acid likepolyester.
• アルデヒドの反応性を利用して、代謝反応が行える。
Reactivity of aldehyde can be used for metabolic reaction.
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There’s no repulsion in glucose
グルコースは安定

D-glucose

D-mannose28

Combustion energy of glucose is converted to ATP’s chemical energy

Prebiotic synthesis of glucose
生命によらない糖合成
step 1step 2

2001 Viva Origino 119.

In reality: step 1

 C3 compounds was enriched.
 D-GA was selected.

In reality: step 2

Possible aldoses:
8 x 2 (D-GA or L-GA)= 16 kinds

ketosealdoseStable hexoses
were chosen by life

2001 Viva Origino 119.

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animaltrehalose昆虫
bacteria

glucose
棘皮動物～哺乳類

plantsSucrose
植物

fungi
archaeaalgae

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Energy media in vessels of multicellular organisms
多細胞生物のエネルギーメディア
Non-reducing sugars were chosen !

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Quiz:For diabetes, please ask questions
from the standpoint of evolutionary
medicine and suggest a cure.
糖尿病について、進化医学の立場から質問をし、治療法を提案してください。
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