Effects of environmental chemicals on energy metabolism and insulin secretion

Transcription

1 Effects of environmental chemicals on energy metabolism and insulin secretion Barbara E. Corkey, Jude T. Deeney, Karel Erion, Nathan Burritt and Orian Shirihai Obesity Research Center Boston University School of Medicine

2 The Problem There is neither cure nor understanding of obesity and diabetes Many proteins and organs implicated-none sufficient Perhaps our current focus on insulin resistance is wrong

3 The Road from Hyperinsulinemia to Redox Regulation and ROS Is hyperinsulinemia the problem? Can any changes in our environment cause an increase in basal insulin secretion? What causes basal insulin secretion? Could these changes influence other organs to explain the multi-organ nature of diabetes?

4 T2DM Patients Have Insulin Levels 900% of Normal Pories, et al. Surgical treatment of obesity and its effect on diabetes. 10 year follow-up. Am. J. Clin. Nutr. 55: 582S-585S, 1992

5 Plasma Glucose (mmol/l) Plasma Insulin (µmu/ml) Days Insulin Minipump in Rats Hyperinsulinemic Control Hyperinsulinemic Control 10 *** * *** * Glucose OK Time (min) Time (min) Juan et al Metabolism 48:

6 Weight Change (%) Lead-in Period Body Weight Difference Between DZ 0 and Placebo Groups Glucose OK Placebo Diazoxide Weeks Alemzadeh R et al. JCEM 1998;83:

7 Is this Insulin Resistance or Hypersecretion? Both! But which comes first?

8 Hyperinsulinemia: A Model ß-Cell Hypersecretion Hyperinsulinemia Obesity and Diabetes Insulin Resistance

9 Interpretation Obesity, diabetes and FFA cause hypersecretion and insulin resistance Either can be primary. So why focus on resistance? Insulin infusion causes insulin resistance Inhibition of insulin secretion improves resistance and increases weight loss Normoglycemia is maintained

10 Insulin Resistance may be Beneficial Insulin resistance may be an adaptive response to maintain normoglycemia in the presence of high insulin Improving insulin sensitivity, without diminishing hypersecretion, may cause hypoglycemia!

11 Hyperinsulinemia as Problem? 1. What might cause insulin secretion in the absence of a stimulatory fuel? 2. How do these agents stimulate secretion? 3. Is ROS essential and sufficient for secretion? Can secretion be stimulated by increasing redox?

12 Comparison of GSIS in Rat Islets Cultured in 11 mm Glucose ± Oleate 20 Insulin (% content/hour) S 0.5 = 8.5 S 0.5 = Oleate + Oleate Glucose (mm) Erion et al unpublished data

13 Food Today Processed food 4,000 new agents Almost none evaluated as causes of diabetes or obesity

14 Fruits and Vegetables have Changed Fruits 27% less zinc Meats 41% less calcium more iron Apples and oranges 67% less iron Broccoli 75% less calcium Spinach 96% less copper Rutabaga 110% more phosphorus David Thomas 1991

15 Plastics in Food Salad dressing and cooking oil bottles made from PVC (polyvinyl chloride) Soda bottles, water bottles, peanut butter jars and cooking oil bottles made from PET (polyethylene terephthalate) Meat trays, foam take-out food containers and cups, foam packing materials made from polystyrene (PS)

16 Hyperinsulinemia as Cause Factor X ß-Cell Hypersecretion Hyperinsulinemia Obesity and Diabetes Insulin Resistance

17 HTS of Environmental Agents

18 Mono-Acylglycerides (MG) MG are formed in the gut by release of FFA in the 1 and 3 positions of TG In cells via release of a fatty acid from DG, by DGL or HSL LPL by release of FFA in positions 1 and 3. Commonly added to food products as emulsifiers and preservatives

19 Insulin (fmoles/5000 Islet cells) MOG Stimulates Basal Secretion MOG (µm) Saadeh et al PLOSone e Epub 2012 Jan 17

20 Insulin (ng/well) Artificial Sweeteners Affect Insulin Secretion in Dissociated Rat Islets G 9G 15G ** * * * Control Sucralose Aspartame Saccharin Ali Al-Saleh Thesis, unpublished

21 ng Insulin/ 1e 6 cells /hr Iron Induces Insulin Secretion in G 12 G INS-1 Cells Transferrin µm Iron Ferrante, Deeney. Unpublished.

22 1. What Agents Cause Insulin Secretion in the Absence of a Stimulatory Fuel? MOG, a lipid food emulsifier and preservative Saccharin, an artificial sweetener Iron, an essential mineral

23 Hyperinsulinemia as Problem? 1. What agents cause insulin secretion in the absence of a stimulatory fuel? 2. How do these agents stimulate secretion? 3. Is ROS essential and sufficient for secretion? Can secretion be stimulated by increasing redox?

24 % increase in fluorescence % increase in fluorescence Effect of MOG and Glucose on Rat Islet REDOX State MOG Glucose mm Glucose Time (min) Time (min) (min) (min) Saadeh et al PLOSone e Epub 2012 Jan 17

25 Change from baseline HyPer fluorescence ratio HyPer Area Under Curve ROS is Generated by MOG MOG Basal Time (min) 0 Basal MOG Saadeh et al PLOSone e Epub 2012 Jan 17

26 2. How Do These Agents Stimulate Secretion? Through changes in redox Through changes in ROS Diazoxide does not inhibit Ca 2+ does not change

27 Hyperinsulinemia as Problem? 1. What agents cause insulin secretion in the absence of a stimulatory fuel? 2. How do these agents stimulate secretion? 3. Is ROS essential and sufficient to cause secretion? Can Secretion be Stimulated by Increasing Redox?

28 Insulin (pmol/10 6 cells) Effect of ROS Scavengers on Insulin Secretion from INS-1 cells 6 5 Control NAC 10mM 16 Control Res 100 µm G 2G MOG 100 µm 6G 0 2G 2G 12G MOG 100 µm Saadeh et al PLOSone e Epub 2012 Jan 17

29 Insulin Secretion (ng/ml) H 2 O 2 Increases Insulin Secretion in INS-1 Cells 60 * 30 * * * * * * 0 Glucose (mm) H 2 O 2 (µm) DEM (mm) Pi et al, Diabetes 2007

30 3. Is ROS Essential and Sufficient? Can Secretion be Stimulated by Increasing Redox? Yes

31 Summary and Implications 1. Hyperinsulinemia can initiate insulin resistance 2. Environmental agents increase insulin secretion in the absence of a stimulatory fuel. 3. These agents stimulate secretion via changes in redox and ROS. ROS is essential and sufficient. 4. Agents are transported to cells via the circulation and can interact with all organs. 5. Agents could impact other organs similarly.

32 RFU RFU ROS Production in Hepatocytes control GSH -200 mv GSH / GSSG -140 mv -110 mv -80 mv -50 mv GSSG CyS / CySS Control CyS -150 mv -80 mv 0 mv CySS oxidized oxidized Laura Nocito et el PLoSone, in press

33 Do Changes in Redox or ROS Alter Function?

34 nmols Glucose/10 6 cells Hepatic Glucose Production L-Ala ctrol CyS -150 mv -80 mv 0 mv CySS oxidized Laura Nocito et el PLoSone, in press

35 Redox and ROS Affect Function Increasing extracellular SH, L/P or ß/A decreases intracellular redox and ROS production Decreases in redox increase ROS and inhibit hepatic glucose production and adipocyte lipolysis and TG synthesis

36 Cytosol Muscle ß-Hydroxybutyrate (ß)+ NAD = Acetoacetate (A) + NADH Mitochondrion Lactate (L) + NAD = Pyruvate (P) + NADH SS(GSSG) + NADPH = SH(GSH) + NADP Blood Stream L P ß A = 10 =1 SH(Cysteine) SS(Cystine) Lactate + NAD = Pyruvate + NADH SS(GSSG) + NADPH = SH(GSH) + NADP Liver Cytosol ß-Hydroxybutyrate + NAD = Acetoacetate + NADH Mitochondrion

37 Eating too much and exercising too little causes obesity. We forgot the most important variable: involuntary control of energy metabolism Hibernating mammals: 4x decrease in EEx Migrating birds: 7x increase in EEx Children prior to 1980s and lean individuals

38 Variations in Energy Efficiency Vermont prisoner study*: lean individuals required cal/d to gain 20% excess wt: increase energy expenditure Dieters decrease energy expenditure Cells exposed to excess nutrient develop proton leak: increase energy expenditure *Salans, Horton, Sims 1

39 Variations in Energy Efficiency Can be induced by excess nutrients via a proton leak Current hypothesis is that ROS can control both energy efficiency and respiration Dysregulation of energy efficiency rather than overeating may cause obesity

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