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International Journal of Human Nutrition and Functional Medicine

www.IntJHumNutrFunctMed.Org

2015 Final PDF

What have been your main areas of research? How did

you become interested in studying mitochondria and

the effects of toxic chemicals on bioenergetics?

I developed radioimmunoassays during my PhD course,

studying hormone (including insulin) measurement. After

being appointed as a faculty staff member in Department

of Internal Medicine, I had an opportunity to do research

in United States in my choice of field for 2 years.

I elected first to study endocrine hypertension at

Boston University (with J Melby) by the suggestion of

Professor Min. Dr Melby had an idea that low-renin

hypertension (a special form of hypertension) is due to

some unknown chemical compound in blood, produced by

our body. Recently a substance known as endocrine

disrupting chemical (EDC), Bisphenol A, has been

reported to increase blood pressure. I studied with rat

adrenal cytosol to pick up that signal, but could not find

evidence.

In 1980 I moved to Joslin Diabetes Research

Center to get exposure to the diabetes field. I studied with

Professor Thomas T Aoki on the energy substrate

metabolism in subjects with diabetes and during exercise.

I started to realize the importance of mitochondrion at that

time, and I found that glucose was not burned completely

as it underwent mitochondrial metabolism (TCA cycle

and electron transport chain). Insulin's stimulation of all

the process suggested a new concept at that time—insulin

resistance. After coming back to Seoul, I found I could not

use any of those high-tech methods, due to lack of money,

machines, and other contingencies.

Then I was exposed to the epidemiology of

diabetes by participating in the International Diabetes

Federation/WHO epidemiology training course held in

Cambridge in 1983. Leaders in diabetes epidemiology,

including Peter Bennet, US NIDDK, told me about the

current state of diabetes research. I was surprised to find a

lack of understanding among diabetes experts on the

cause(s) of diabetes. I started to think

my own way

by the

late 1980s. The following were key considerations, which

I published in

Journal of the Korean Diabetes Association

in early 1994.

1) It was self-evident that environmental factor(s) are the

most important causative agent of the diabetes

epidemic. The word ‘epidemic’ suggested it.

2) It was also apparent that the agent is ‘not-infectious’.

3) The factor or factors causing diabetes were being

introduced by societal modernization/westernization. I

thought at first fungal toxin(s) might be the major

player, which proved very unlikely. I could not figure

them out easily.

Then one friend educated me that free radical damage in

mitochondrial DNA (mtDNA) occurs almost 10-times

faster than in nuclear DNA. In late 1980s, mutation in

mtDNA (now known as MELAS mutation at the 3243

position) had just been reported to cause diabetes.

4) I started to look at mitochondria as a target for the

unknown environmental factor causing diabetes. Very

few people were studying mitochondria at that time. It

occurred to me if mitochondrial damage is caused by

the chemicals, it could explain insulin deficiency,

insulin resistance, and genetic susceptibilities.

To understand the state of mtDNA, I simply took

leukocytes of diabetic subjects and let my students do

southern blot of mtDNA. We found that mtDNA density

was lower in diabetics than in healthy controls. This was

in 1994. Then by early 1995, Dr Ronald Khan, Director of

Joslin Research Center, reported that mitochondrial DNA

abnormality in diabetes is indeed low, but concluded it is

secondary

to the diabetic state. However, our group

appreciated the possibility that mitochondrial dysfunction

or mtDNA abnormality could be the

cause

of diabetes, as

demonstrated by mtDNA mutation. Dr Khan's report was

huge blow to me, but also it provided an opportunity—

very little competition. Gerry Shulman and his colleagues

at Yale University were one of few groups who

continuously reported the presence of mitochondrial

dysfunction in insulin resistance. However, the question

of whether it is primary or secondary remains with us day.

By 2000, my group made some advances. Most

importantly, we found that mtDNA depletion in peripheral

blood precedes the onset of diabetes in a community-

based cohort by using the so-called nested case-control

design. Furthermore, reduced mtDNA level were found to

correlate with blood pressure, abdominal obesity, and

other parameters of metabolic syndrome.

We also established that mtDNA is an

independent genetic susceptibility factor of diabetes. We

made mtDNA-depleted cells and showed they are insulin-

resistant. We were among few groups who appreciated

this. It was time to think about "

what causes the

mitochondrial dysfunction?

" I looked at an obesity map

published by the US CDC, and I saw that the obesity

epidemic occurred mostly around the Mississippi river

valley and eastern states. I realized that pesticide use

might be a cause. Atrazine was the most widely used

chemical, herbicide. It was known to cause mitochondrial

damage. We started to feed atrazine to rats to see if it

"We made mtDNA-depleted cells and showed they are

insulin resistant. Few people recognized those works. It was

time to think "what caused the mitochondrial dysfunction?" I

looked obesity map published by US CDC. Obesity epidemic

occurred mostly around the Mississippi river valley and

eastern states. I realized pesticides use might be a cause.

Atrazine was the most widely used chemical, herbicide. It

was known to cause mitochondrial damage."