THE ROLE OF TOXICITY IN THE EPIDEMIC OF OBESITY AND METABOLIC - PowerPoint PPT Presentation

THE ROLE OF TOXICITY IN THE EPIDEMIC OF OBESITY AND METABOLIC DISORDERS Paul Mannion

OBESITY AND DIABETES EPIDEMIC IN AUSTRALIA Australia’s Health 2012 in brief. Australian Institute of Health and Welfare http://www.aihw.gov.au/WorkArea/DownloadAsset.aspx?id=10737422173

Dr Mark Hyman, 2014

ARE ALL CALORIES REALLY CREATED EQUAL?

IS IT LACK OF EXERCISE, OR IS IT THE FOOD?

Culver AL. et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med. 2012 Jan 23;172(2):144-52.

STATINS INCREASE RISK OF DIABETES BY 47% OVER THREE YEARS Culver AL. et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med. 2012 Jan 23;172(2):144-52.

BUT WAIT, THERE’S MORE Although lifestyle changes have contributed to the increase in the prevalence of chronic diseases in developing countries, obesity, T2DM, and other diseases associated with insulin resistance are increasing in developed countries where there have been no recent changes in diet or physical activity. Lim S, Cho YM, Park KS, Lee HK. Persistent organic pollutants, mitochondrial dysfunction, and metabolic syndrome. Ann N Y Acad Sci. 2010 Jul;1201

THIS TIME THE PESTICIDES ARE SAFE… “About once in every generation we start using a different kind of pesticide…one reason is because of resistance, the other is that negative effects on human health and the environment start to emerge.”

Jones Beach 1948

CHEMICAL DISASTERS REVEAL STARTLING FINDINGS

TOXIC NURSES FOUND TO HAVE 3x HIGHER RISK OF T2DM Incide dence of e of Type 2 pe 2 diabet diabetes in in nurses f from om the N the NHL stu study 10 es etes 8 iabet Tertile 1 - (27.5 6 e 2 Dia ng/g HCB) 4 Tertile 2 - (37 ng/g Type 2 HCB) 0 of T Tertile 3 -(51.5 ent o Tertile of HCB concentration (ng/g ng/g HCB) Percen lipids) HCB b blood c d concentr ntrati ation T Terti tile Extrapolated from Wu H. et al. Persistent organic pollutants and type 2 diabetes: a prospective analysis in the nurses' health study and meta-analysis. Environ Health Perspect. 2013 Feb;121(2):153-61.

A ‘COCKTAIL’ OF POPs CAN TRIPLE THE PREVALANCE OF PREDIABETES Cumulative effect of all five POPs (POLL5) Ukropec J. et al. High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail. Diabetologia. 2010 May;53(5):899-906

DIABETES, CARDIOVASCULAR DISEASE INCREASE WITH PCB EXPOSURE Lind L, Lind PM. Can persistent organic pollutants and plastic-associated chemicals cause cardiovascular disease ? J Intern Med. 2012 Jun;271(6):537-53.

WHAT ARE POPs? • Persistent organic pollutants (POPs) are characterised by their ability to persist in the environment, their low water and high lipid solubility and their bio-magnification in the food chain • POPs include – Organochlorines, DDT, PCBs, dioxins, dibenzo-p-furans (PCDFs), polybrominated biphenyls (PBB), hexachlorobenzene (HCB) • POPs can travel great distances and can end up in countries other than those in which they were produced Magliano DJ et al. Persistent organic pollutants and diabetes: A review of the epidemiological evidence. Diabetes Metab. 2013 Nov 18. pii: S1262-3636(13)00179-1

AROUND 95% OF POPs INTAKE IS THROUGH DIETARY INTAKE OF ANIMAL FATS Rysavy NM, Maaetoft-Udsen K, Turner H. Dioxins: diagnostic and prognostic challenges arising from complex mechanisms. J Appl Toxicol. 2013 Jan;33(1):1-8 Magliano DJ et.al. Persistent organic pollutants and diabetes: A review of the epidemiological evidence. Diabetes Metab. 2013 Nov 18. pii: S1262-3636(13)00179-1

METABOLIC DISORDERS LINKED TO EDCs? Casals-Casas C, Desvergne B. Endocrine disruptors: from endocrine to metabolic disruption. Annu Rev Physiol 2011;73:135-62

TBBPA DISRUPTS THYROID FUNCTION Decherf S, Demeneix BA. The obesogen hypothesis: a shift of focus from the periphery to the hypothalamus. J Toxicol Environ Health B Crit Rev. 2011;14(5-7):423-48.

TOXIN EXPOSURE AFFECTS HYPOTHALAMIC REGULATION OF ENERGY Decherf S, Demeneix BA. The obesogen hypothesis: a shift of focus from the periphery to the hypothalamus. J Toxicol Environ Health B Crit Rev. 2011;14(5-7):423-48.

MITOCHONDRIAL TOXINS Lim S, Cho YM, Park KS, Lee HK. Persistent organic pollutants, mitochondrial dysfunction, and metabolic syndrome. Ann N.Y. Acad Sci 2010;1201:166-176

INSULIN RESISTANCE LINKED TO MITOCHONDRIAL DYSFUNCTION Lim S, Cho YM, Park KS, Lee HK. Persistent organic pollutants, mitochondrial dysfunction, and metabolic syndrome. Ann N.Y. Acad Sci 2010;1201:166-176

IS METABOLIC SYNDROME AN ADAPTIVE RESPONSE TO MITOCHONDRIAL DAMAGE? The development of obesity, hyperglycaemia, and hypertension might be viewed as compensatory responses to the decreased mitochondrial unit of the body: maintaining core temperature by decreasing heat loss and increasing heat production, increasing the availability of fuels, and stimulating energy metabolism as a whole through activation of the sympathetic nervous system. Lee HK, et.al. Mitochondrial dysfunction and metabolic syndrome-looking for environmental factors. Biochim Biophys Acta. 2010 Mar;1800(3):282-9

DIOXIN ASSOCIATED WITH MITOCHONDRIAL DAMAGE AND DIABETES TCDD = Tetrachlorodibenzodioxin Charcoal stripped human serum NFG-normal fasting glucose IFG - impaired fasting glucose DM –diabetes mellitus Both TCDD and patient sera decreased the ATP turnover rate and mitochondrial total respiratory capacity. *P < 0.05, **P < 0.01 vs. control, n =4. Park WH et.al Novel cell-based assay reveals associations of circulating serum AhR-ligands with metabolic syndrome and mitochondrial dysfunction. Biofactors. 2013 Jul- Aug;39(4):494-504

POPs AFFECT GENE EXPRESSION & LEAD TO INSULIN RESISTANCE Ruzzin J et al. Persistent organic pollutant exposure leads to insulin resistance syndrome. Environ Health Perspect. 2010 Apr;118(4):465-71.

POPs DRIVE FATTY LIVER AND VAT HF – high fat diet HFR – High fat diet containing refined fish oil (Atlantic salmon) HFC – high fat diet containing crude fish oil (Atlantic salmon) HF HFR HFC Chow Ruzzin J et al. Persistent organic pollutant exposure leads to insulin resistance syndrome. Environ Health Perspect. 2010 Apr;118(4):465-71.

POPs CAN MAKE FAT ‘SICK’ Michele La Merrill M, et al. Toxicological function of adipose tissue: focus on persistent organic pollutants. Environ Health Perspect, 2013; 121:162–169.

POPs HIDE AWAY IN FAT TISSUE AND CAN SLOWLY LEAK OUT Michele La Merrill M, et al. Toxicological function of adipose tissue: focus on persistent organic pollutants. Environ Health Perspect, 2013; 121:162–169.

THE FAT LOSS PARADOX It has been suggested that weight loss induces a significant increase in plasma organochlorine levels in humans. This rise in plasma organochlorine concentration has also been associated with a decrease in T3 concentration, resting metabolic rate and skeletal muscle capacity for fat oxidation. Lim S, Cho YM, Park KS, Lee HK. Persistent organic pollutants, mitochondrial dysfunction, and metabolic syndrome. Ann N Y Acad Sci. 2010 Jul;1201:166-76

FAT LOSS PATIENTS NEED SUPPORT TO PREVENT POPs DAMAGE When fatty acids are released from adipose tissue, POPs are released simultaneously. This can damage mitochondria in endocrinologically active tissues such as the liver and muscle. Thus, POPs may decrease mitochondrial oxidative capacity in various organs. Lim S, Cho YM, Park KS, Lee HK. Persistent organic pollutants, mitochondrial dysfunction, and metabolic syndrome. Ann N Y Acad Sci. 2010 Jul;1201:166-76

GGT LEVELS RISE IN RESPONSE TO TCDD LEVELS Impaired fasting glucose and Diabetes mellitus Park WH et.al Novel cell-based assay reveals associations of circulating serum AhR-ligands with metabolic syndrome and mitochondrial dysfunction. Biofactors. 2013 Jul-Aug;39(4):494-504

GLUTATHIONE ESSENTIAL FOR DETOXIFICATION OF XENOBIOTICS Lee DH, Steffes MW, Jacobs DR Jr. Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes ? Diabetologia. Mar 2008; 51(3): 402-7.

EVEN LOW EXPOSURE DEPLETES GLUTATHIONE • Even at low doses POPs induce responses like phase I, phase II, and phase III xenobiotic metabolism pathways. • In particular, phase II glutathione (GSH) conjugation can lead to chronic consumption and depletion of intracellular GSH. • Intracellular GSH depletion can cause mitochondrial dysfunction which is closely related to inflammation and ectopic fat accumulation and type 2 diabetes. Lee DH, Porta M, Jacobs DR Jr, Vandenberg LN. Chlorinated Persistent Organic Pollutants, Obesity, and Type 2 Diabetes. Endocr Rev. 2014 Jan 31

N-ACETYLCYSTEINE REPLENISHES LOW GSH IN SUBJECTS WITH OXIDATIVE STRESS 0.8 0.7 ∆ erythrocyte GSH after 12 weeks 0.6 (µmol/g Hg) 0.5 0.4 0.3 0.2 0.1 0 No treatment 200 mg NAC 400 mg NAC 800 mg NAC Kasperczyk S, et al. The administration of N-acetylcysteine reduces oxidative stress and regulates glutathione metabolism in the blood cells of workers exposed to lead. Clin Toxicol (Phila). 2013 Jul; 51(6): 480-6.