Yallow and Berson found high serum insulin in type diabetes, thus insulin resistance : common underlying biochemical abnormality

1. Yallow and Berson found high serum insulin in type 2 diabetes, thus insulin resistance : common underlying biochemical abnormality

• 1. Yallow and Berson found high serum insulin in type 2 diabetes, thus insulin resistance : common underlying biochemical abnormality

• 2. Molecular approach (insulin receptor and post-receptor mechanisms) was not successful

• 3. Epidemiologic approach by establishing a disease entity (syndrome X) proposed by Reaven (1988)

• 4. WHO experts gave new name; metabolic syndrome (1998)

Genetic cause (thrifty genotype hypothesis. Neel JV, 1962)

• Genetic cause (thrifty genotype hypothesis. Neel JV, 1962)

• Fetal malnutrition (thrifty phenotype hypothesis. Barker DJP and Hales CN, 1992)

• 3 Mitochondrial dysfunction (Lee HK et al, 2006)

• Environmental chemicals (Baillie-Hamilton PF, 2002) and POPs (Lee DH et al, 2006)

As genes did not change, something in the environment should have caused it

• As genes did not change, something in the environment should have caused it

• Causative agent(s) should be not infectious

• Introduced by industrialization/ westernization/ coca-cola-rization?

• Diabetogenic drug, streptozotocin damaged cell as NO donor

• Mitochondrion is most vulnerable target of free radicals

mtDNA 0.41 +/- 0.06 (n = 12) pmol of 8-OHdG per ug

• mtDNA 0.41 +/- 0.06 (n = 12) pmol of 8-OHdG per ug

• nDNA 0.025+/- 0.004 (n = 4)

• 16 times lower level of 8-OHdG in nuclear DNA

• Oxidative damage should leave clue in mtDNA

• What the hell is mitochondria and its DNA?

mtDNA density decrease precede the development of diabetes in Yochon cohort, 1998

• mtDNA density decrease precede the development of diabetes in Yochon cohort, 1998

• Medical student cohort (KU Lee et al)

• Birth weight and mtDNA density (YY Lee, YA Sung): thrifty phenotype hypothesis

• mtDNA variations and insulin resistance (Asians)

• 16189 T>C,

• haplogroups N9a (resistant)

• haplogroups B and F (sensitive)

• (In collaboration with M Tanaka et al, K Nanjo et al)

Genetic cause (thrifty genotype hypothesis. Neel JV, 1962)

• Genetic cause (thrifty genotype hypothesis. Neel JV, 1962)

• Fetal malnutrition (thrifty phenotype hypothesis. Barker DJP and Hales CN, 1992)

• 3 Mitochondrial dysfunction (Lee HK et al, 2006)

• Environmental chemicals (Baillie-Hamilton PF, 2002) and POPs (Lee DH et al, 2006)

This association was confirmed in Greenland (Inuit), Taiwan, Japan, Native American, Slovakia and Belgium (Dirink E et al. Obesity, 2010).

• This association was confirmed in Greenland (Inuit), Taiwan, Japan, Native American, Slovakia and Belgium (Dirink E et al. Obesity, 2010).

• An environment-wide association study (EWAS) on type 2 diabetes mellitus supported (Chirag J et al, PLoS One 2010)

• Confirmed in experimental studies (Lim S, PLoS One, 2009; Ruzzin J et al, Environ Health Persp, 2009)

Establishing cause-effect relationship between xenobiotics exposure and MS

• Establishing cause-effect relationship between xenobiotics exposure and MS

• 3 Koch’s postulates

• Etiologic treatment: drug development and clinical trials

POPs are very diverse, small, slowly act, dangerous to handle and ---

• POPs are very diverse, small, slowly act, dangerous to handle and ---

• Current detecting methods are too expensive

• Need cheap and valid method (for diagnosis): i.e. CALUX (chemically activated luciferase expression) assay

• Best way to eliminate toxins (evidence-based detoxification therapy)

Park KS, Cho YM, Lim S, KimPak Y, Lee W, and many collaborators, Korea

• Park KS, Cho YM, Lim S, KimPak Y, Lee W, and many collaborators, Korea

• Wei Y-H, Taiwan

• Nanjo K, Tanaka M. Japan

• Members of Molecular Diabetology in Asia