Are Fake Sugars Contributing to the Obesity Epidemic? Prenatal and early-life exposure to non-nutritive sweeteners and cardiometabolic health

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1 Are Fake Sugars Contributing to the Obesity Epidemic? Prenatal and early-life exposure to non-nutritive sweeteners and cardiometabolic health Meghan Azad, PhD Children s Hospital Research Institute of Manitoba Department of Pediatrics & Child Health, University of Manitoba Canadian Healthy Infant Longitudinal Development (CHILD) Study meghan.azad@umanitoba.ca Oregon Nutrition Day May 2017

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3 Developmental Origins of Allergies Asthma Obesity 1 in 4 Canadians have seasonal allergies 1 in 13 have food allergies Canadian Allergy, Asthma and Immunology Foundation & 2013 SCAAALAR survey 1 in 6 Canadian children have asthma Public Health Agency of Canada (2007). Life and breath: Respiratory disease in Canada. 1 in 3 Canadian children are overweight or obese Overweight and obesity in children and adolescents: Results from the 2009 to 2011 Canadian Health Measures Survey

4 The Canadian Healthy Infant Longitudinal Development (CHILD) Study How do genes and the environment influence child health and development? $30M Invested 500,000 Samples: Blood, Urine, Stool, Nasal Swabs, Dust, Breast Milk 200,000 Questionnaires 3600 Families 40+ Researchers 20+ Disciplines 5(+) Years Follow-Up 93% Retention N=3500

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6 (Putignani et al. Pediatric Research :1)

7 Non-nutritive sweeteners (NNS) AKA: Artificial / Low-Calorie / No-Calorie / Intense Sweeteners Sucralose 600x Saccharin 300x Aspartame 200x Acesulfame-K 200x Rebaudioside A 300x

8 NNS Consumption: Common and Increasing 25.1% of children and 41.4% of adults consumed NNS in 2009 Most consumers use daily Primarily in beverages, but increasingly (unknowingly?) in foods Higher for: Females, Non-Hispanic White, Obese, High income Sylvetsky et al. J Acad Nutr Dietetics 2017 Sylvetsky et al. AJCN 2012 Swithers Trends Endocrinol Metab 2013

9 At this time, there are insufficient data to determine conclusively whether the use of LCS to displace caloric sweeteners in beverages and foods reduces added sugars or carbohydrate intake, or benefits appetite, energy balance, body weight, or cardio-metabolic risk factors. - Joint American Diabetes Association and American Heart Association Position Statement, 2012 There is a paucity of evidence on long-term health effects in humans from nonnutritive sweeteners, particularly resulting from exposure initiated in childhood. - Nutrition Standards for Foods in Schools, US Institute of Medicine, 2007

10 NNS and Cardiometabolic Health?

11 Proposed Mechanisms: NNS and Cardiometabolic Health 1. Sweet taste receptor activation: glucose absorption, insulin secretion 2. Uncoupling of sweet taste / calories: disrupted energy homeostatsis 3. Gut microbiota dysbiosis: increase host energy harvest 4. Sweet taste preferences 5. Compensation: Diet Coke / Big Mac syndrome

12 NNS and Incidence of Type 2 Diabetes (Adults) 9 prospective cohorts (N=400,571 adults) with 4 to 24 yrs follow up 14% increased risk (Pooled RR 1.14, 95%CI 1.05 to 1.25) Azad et al. CMAJ 2017 (Accepted)

13 Azad et al. CMAJ 2017 (Accepted) NNS & Cardio-metabolic Health (Adults)

14 NNS and Cardiometabolic Health (Adults) Systematic Review & Meta-Analysis 37 Studies (406,000 adults) with >6 months follow up Randomized controlled trials do not clearly support the intended benefits of NNS for weight management. Observational data suggest routine NNS intake may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of NNS.? Azad et al. CMAJ 2017 (Accepted)

15 NNS & DOHaD? Little evidence. Mostly in rodents. With extreme doses.

16 ? Only 8 eligible studies (total n=15,641 children) 6 cohorts: increasing weight gain or fat mass accumulation with increasing NNS (n=3) or no association (n=3) 2 RCTs: contradictory effects on weight change in children receiving NNS No eligible studies evaluated prenatal or infant NNS exposure.

17 Sugar-Sweetened (SS) and Artificially Sweetened (AS) Beverage Consumption During Pregnancy Food Frequency Questionnaire in 2 nd trimester 29% consumed AS Beverages 5% consumed AS Beverages daily

18 Daily consumption of ASBs during pregnancy associated with 2-fold increased risk of infant overweight

19 Population N=2413 Adjusted* Odds Ratio for Infant Overweight (Daily ASB vs. Rarely) Interpretation Overall 2.19 (1.23 to 3.88) 2-fold increased risk Mechanism? Do effects depend on Type of NNS? Timing of Exposure? Maternal BMI Normal Weight Overweight Infant Sex Female Male Breastfeeding < 6 months 6 months 2.21 (0.81 to 6.06) 1.96 (0.81 to 4.76) 0.45 (0.09 to 2.33) 3.07 (1.41 to 6.69) 2.58 (1.10 to 6.07) 1.07 (0.31 to 3.67) NOT explained by confounding by maternal obesity Sex difference: stronger association in males Breastfeeding >6 months mitigates association

20 Prenatal exposure to NNS and the development of childhood obesity CHRIM Operating Grant Meghan Azad & Vern Dolinsky Prenatal Exposure to Artificial Sweeteners CHILD Study: Diet questionnaire Mouse Model: Controlled exposure Metabolic Programming Glucose tolerance Insulin sensitivity Endocrine signaling Adipogenesis Gut microbiome Appetite regulation Food preferences Weight Gain, Obesity, Metabolic Health CHILD Study: Early childhood Mouse Model: Full lifespan Maternal Obesity, Diabetes, Diet Quality, Breastfeeding, Postnatal Diet, Physical Activity

21 NNS consumption during pregnancy: impact on infant gut microbiome and metabolism in the CHILD cohort CIHR Operating Grant Meghan Azad Claire Arrieta-Mendez Laura Sycuro Atul Sharma

22 Summary NNS consumption is common and increasing, including among children and pregnant women NNS intake associated with higher cardiometabolic risk in adults More research needed to establish causality in humans Few studies have examined impact of NNS in early life Rodent studies: possible DOHaD effects CHILD Study: prenatal NNS exposure may influence infant weight gain Knowledge Gaps NNS Type? Lactational exposure? Long term effects? Substitution of sugar for NNS?

23 Acknowledgements Azad Lab Faisal Atakora, Lorena Vehling, Deborah Chan, Michelle La CHILD Study Manitoba: Allan Becker, Rishma Chooniedass & Team National: Malcolm Sears, Diana Lefebvre (McMaster) & Team Collaborators Atul Sharma, George & Fay Yee Centre for Healthcare Innovation Ehsan Khafipour, Shirin Moosavi (U. Manitoba) Catherine Field, Sue Goruck (U. Alberta) Lars Bode (U. California San Diego) Vern Dolinsky (U. Manitoba)