1. LOW CALORY SWEETNERS
AND
WEIGHT
Dra Pilar Riobó MD, PhD
Associate Head
Endocrinology and Nutrition Department
Hospital Fundacion Jimenez Diaz-Capio.
Madrid
FENS Meeting 2011

2. Overweight and
Obesity are Epidemic

3. Obesity and overweight have been reported to be
associated with decreases in life expectancy.
Non-smoking women Smoking women Non-smoking men Smoking men
Framingham Heart Study
13.7
Non-smoking women lost 7 years,
5.82 Non-smoking men 5.8 years
13.3
7.08
0 5 10 15
Implications of obesity at age 40 on life
expectancy. Peeters, A, et al. Ann Int Med 2003;138:24-32

4. Obesity and other risk factors
Blood HDL-C PCRP
pressure
pro-thrombotic
T-Cholesterol-t OBESITY factors
Insulín
Diabetes Resistance
TG,Lp(a)
sdLDL

5. Diabetes epidemic
300 millions
300
250
Millones de personas
200
154 millionsio
135 millions
150
100
50
0
1995 2000 2025
King H. Diabetes Care 1998

7. Obesity is associated with increased risk
for most cancers (ACS)
1.44
Multiple myeloma (>35)
1.46
Colon & Rectum (>40)
Type of Cancer (Highest BMI category)
1.51
Ovary (>35)
1.68
Liver (>35)
1.88
All Cancers (>40)
1.95
Non-Hodgkin’s Lymphoma (>35)
2.12
Breast (>40)
2.13
Gallbladder (>30)
2.51*
All Other Cancers (>40)
2.64*
Oesophagus (>30)
2.76
Pancreas (>40)
3.20
Cervix (>35)
4.75
Kidney (>40)
6.25
Uterus (>40)
0 1 2 3 4 5 6 7 8 9 10 11
Relative Risk of Death (95% Confidence Interval)
Calle E et al. N Engl J Med 2003;348:1625-1638
Mortality from Cancer According to BMI >30->40 for U.S.
Women in the Cancer Prevention Study II, 1982 through 1998

8. The Rising
Rate of
Childhood
Obesity is
Alarming
30% of children are overweight
or at risk for overweight

9. Obesity Today: Future Impact
“Because of increasing rates of
obesity…we may see the first
generation that will be less
healthy and have a shorter life
expectancy than their parents.”
Surgeon General Richard Carmona

10. The Biological Cause of
Obesity is Simple
An imbalance of calories IN
and calories OUT!
But…

11. …The Social Factors that lead
to the Imbalance are Complex
• Changing food habits due to busy lifestyles (no family
meals…)
• Declining physical activity during work and leisure time
• Changing physical environment (urban, safety)
• Decreased sleep duration
• Hedonic and reward aspects of food
• Psychological problems
• Side effects of common drugs

12. Weight Issues
It’s Much More than
ENERGY BALANCE
Social factors play a
role

13. Food Selection:
What’s Important?
89%
Taste
71%
Nutrition
71%
Product Safety
69%
Price
% Saying ”Very Important”
Source: FMI Trends, 2000

14. • Sweet taste permits the
identification of
energy-rich nutrients
• Umami (savoury/meaty taste)
allows recognition of protein
• Salty taste ensures proper
electrolyte balance
• Sour and Bitter tastes
warn against the intake of
potentially poisonous chemicals
Taste has the additional value of contributing to
the overall pleasure and enjoyment of a food

15. Taste results from the stimulation of specialised
cells (TRCs), grouped in clusters or taste buds,
mainly located on the tongue, but also in gut.
Circumvallate papillae, contain
thousands of taste buds.
Foliate papillae, contain hundreds
of taste buds.
Fungiform papillae contain
one or a few taste buds

16. Structure of sucrose and various
artificial sweeteners

17. LCS
Saccharin, discovered in 1878
Cyclamate in Europe (in 1969, banned in the US
due to association with bladder cancer in rats.
Subsequent review of the evidence raised questions
about the trials, but remained unapproved in USA
Aspartame, approved for use in food 1981,
Acesulfame-K
Sucralose
Neotame
Stevia, a herb with intense sweetness

18. Aspartame
Used worldwide in over 6000 products
ADI levels of 50 (FDA)and 40 mg/kg bw/day, (EFSA)
The rise in plasma levels of Phen and aspartic following
administration of aspartame at doses < 50 mg/kg do not
exceed those observed postprandially.
No credible evidence that aspartame is carcinogenic.
No evidence that aspartame will affect nervous system
function, learning or behavior.

19. What are the Consumption
levels of LCS ?
Approved NNS are regarded as “GRAS”
producers and manufacturers are not required to
provide content data on food labels
Data on the amounts of NNS in foods not readily
accessible.

20. Use of Sweetners in USA
(millions tons)

21. Artificial sweetener use and
obesity trends in the United States

22. Safety standards for
consumption of NNS
European Food Safety Agency (EFSA) havs established
Acceptable Daily Intakes (ADI)
20 cans of diet cola for aspartame
 9 to 12 packets of sweetener for saccharin
30 to 32 cans of diet lemon soda for acesulfame-K
6 cans of diet cola for sucralose

23. Calorie savings available by
choosing foods and drinks with LCS
Calories (kcal)
Product With sugar Low calorie
sweeteners
Carbonated soft drinks 330 ml 145 2
Powdered soft drinks 240 ml 86 5
Desserts 240 ml 150 75
Milk shake mix 180 ml 110 50
Fruit yoghurt 180 g 207 81
Table top sweetener tablets 16 1
Table top sweetener powder 16 2

24. Key questions
 Does the replacement of a high energy sweetener
(such as sucrose) with an artificial sweetener (such
as saccharine or aspartame) lead to weight loss?
 Substituting sugar with low calorie sweeteners
may be an efficacious weight management
strategy?
 Does sweetness (with or without energy)
contribute to over-consumption?

25. 2.
.
normal-weight subjects Weight
1 150 g /day soda sweetened
with aspartame HFCS , for 3 wk
7% decrease in
calorie intake
when subjects
drank APM-
sweetened soda
Am J Clin Nutr 90

26. Energy and macronutrient intakes from
ad libitum diet at 0, 5, 10 weeks
After 10 wk, the
sucrose group had
increases in total
energy, sucrose,
and carbohydrate
intakes
and decreases in
fat and protein
intakes
Raben A et al. Am J Clin Nutr 2002 ;76:721

27. Body weight and fat
mass increased in
the sucrose group
(1.6 and 1.3 kg)
and decreased in
the sweetener group
(-1.0 and -0.3 kg)
Raben A et al. Sucrose compared with artificial sweeteners: different effects on ad libitum food intake
and body weight after 10 wk of supplementation in overweight subjects. Am J Clin Nutr 2002 ;76:721

28. PRCT,
160 obese women randomly assigned to
consume or to abstain from aspartame-
sweetened foods and beverages during
16-wk weight-reduction program
a 1-y maintenance program,
and a 2-y follow-up period
no difference in weight loss between groups using
and avoiding aspartame, but the aspartame group
regained significantly less weight
during maintenance and follow-up ( 3 years)
Blackburn et al. AJCN 1997

29. Do artificial sweeteners actually
help reduce weight?
 Replacement of sucrose with aspartame could
result in a decrease in calorie intake, enough to
produce a health benefit.
 Even modest reductions in the intake of calories
can reduce the risk factors associated
with diabetes and cardiovascular
disease

30. But…
 Epidemiologic data suggest the
opposite.
 Several large scale prospective
cohort studies found positive
correlation between artificial
sweetener use and weight gain.

31. Do LCS promote weight gain?
ACS survey
conducted over one year with 78,694 women 50–69 yo
After controlling for initial body weight, those who
used LCS were significantly more likely to gain weight
than non-users.
However, mean weight changes differed by less than
1Kg, so no conclusion was drawn
Despite the conservative interpretation of the data, the
hypothesis generated considerable debate.

32. 6,814 adults, 45–84 years,
Diet soda consumption was assessed by food frequency
questionnaire at baseline (2000–2002).
At least daily consumption of diet soda was
associated with a
36% greater relative risk of incident metabolic
syndrome
and a 67% greater relative risk of incident type 2
diabetes
compared with non consumption
Diabetes Care 32:688–694, 2009

33. The San Antonio Heart Study
OR of becoming
overweight
OR of becoming
obese
Fowler. SP. Et al. Fueling the Obesity Epidemic? Artificially Sweetened
Beverage Use and Long-term Weight Gain . Obesity (2008) 16, 1894–1900.

34. Fueling the Obesity Epidemic? Artificially
Sweetened Beverage Use and Long-term Weight
Gain in the San Antonio Heart Study
Δ BMIs were 47%
greater among artificial
sweetner users
than nonusers
(+1.48 kg/m2 vs. +1.01
kg/m2, P < 0.0001).
Fowler. SP. Et al. Obesity (2008) 16, 1894–1900.

35. Critics
•These are observational studies, not
clinical trials
•The potential confounding of LCS use
for weight control cannot be ruled out
•Prevalence of obesity is higher among
Mexican Americans but use of AS is lower

36. Potential mechanisms blamed
 Dissociating sweetness from calories, LCS could
interfere with physiological responses that control
homeostasis.
 Changing the intestinal environment, LCS could affect
the microbiota and, in turn, trigger inflammatory
processes associated with metabolic disorders.
 Interacting with sweet-taste receptors discovered in
the gut, LCS could affect glucose absorptive capacity
and activate gut sweet-taste pathways that control
incretin release and upregulate glucose transporters.

37. LCS and Appetite
Acute exposure to LCS in vehicles providing no
energy, augments hunger relative to effects of
exposure to the vehicle alone.
Similar effects in a study of comparable design,
using NaCl . 
The phenomenon may be attributable to oral
exposure to a palatable stimulus in the absence
of an energy load

38. Is there any compensation?
It has been told that after ingestion of a
sweetened, non-energy-yielding beverage one
can “compensate” increasing energy intake
•Estimated compensation rate of around
one-third of energy substituted
•Soft drinks around 15%. This is reasonable
as it is likely that energy obtained from
liquids is less satiating
Nevertheless, these compensation values are
derived from short-term studies

39. Effect of preloads containing stevia,
aspartame, or sucrose on food intake, satiety,
and postprandial glucose and insulin levels.
 19 healthy lean and 12 obese
 hunger and satiety levels were similar in all three
conditions.
 In terms of hedonic ratings, participants rated the
preloads containing aspartame as having a more
pleasant taste than the preloads containing stevia
or sucrose.
Anton et al. Effects of stevia, aspartame, and sucrose on food intake, satiety, and
postprandial glucose and insulin levels. Appetite 2010 ; 55(1):37-43

40. Participants did not compensate
(food intake at subsequent lunch and dinner meals
was not increased) when they consumed lower
calorie preloads containing stevia or aspartame
compared to sucrose.
.
Anton et al. Effects of stevia, aspartame, and sucrose on food intake, satiety, and
postprandial glucose and insulin levels. Appetite 2010 ; 55(1):37-43

41. Consumption of stevia in
preloads significantly
lowered postprandial
insulin levels compared
to both aspartame and
sucrose, as well as
postprandial glucose levels
compared to sucrose.
Consumption of aspartame
in preloads reduced
postprandial glucose
compared to sucrose
Anton et al. Effects of stevia, aspartame, and sucrose on food intake, satiety, and
postprandial glucose and insulin levels. Appetite 2010 ; 55(1):37-43

42. Is there any compensation?
The preponderance of evidence in long-
term feeding trials indicates that LCS
results in no change or a reduction in
energy intake

43. Meta-analyses
16 studies
Subjects in 3 trials
were obese
Significant reduction in
energy intake with
aspartame
mean reduction of about
10% of energy intake.
de La Hunty Br Nutr Found
Bull. 2006: 31; 115-128

44. Meta-analyses: 16 studies
Significant reduction in weight
about a 3% reduction in body weight
de La Hunty
Br Nutr Found
Nutr Bull. 2006

46. The meta-analyses demonstrate that using foods and
drinks sweetened with aspartame instead of sucrose
results in a significant reduction in both energy intakes
and body weight.
Rate of weight loss of about 0.2 kg/week.
This is a low but meaningful rate of weight loss and, more
than sufficient to counteract the current average rate of
weight gain of around 0.007 kg/week
de La Hunty A, Gibson S, Ashwell M. A review of the effectiveness of aspartame in helping with weight
control. Br Nutr Found Nutr Bull. 2006: 31; 115-128

47. Sweet taste receptors
a heterodimer of two transmembrane
proteins (T1R2 , T1R3 and gustducin)
has several different binding sites
Present in lingual taste buds, and
GLP-1 secreting L cells of the gut
Respond to caloric sugars and to LCS
Serve as mediators of GLP-1
secretion

48. The Incretin Effect: insulin response is greater when
glucose is administered orally vs. IV infusion.
Control Subjects Patients With Type 2 Diabetes
(n=8) (n=14)
0.6 0.6
80 80
Incretin The incretin effect
Effect 0.5 is diminished 0.5
in type 2 diabetes.
60 60
IR Insulin, mU/L
IR Insulin, mU/L
0.4 0.4
nmol / L
nmol/L
40 0.3 40 0.3
0.2 0.2
20 20
0.1 0.1
0 0 0 0
0 60 120 180 0 60 120 180
Time, min Time, min
Oral glucose load Intravenous (IV) glucose infusion
IR=insulin resistance.
Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag. 12

49. Role of Incretins in Glucose Homeostasis
Ingestion of food
Pancreas
Glucose-dependent
 Insulin from β cells Glucose uptake
by muscles
Release of gut (GLP-1 and GIP)
hormones — Blood glucose in
GI tract incretins* fasting and
β cells postprandial states
Active α cells
GLP-1 & GIP Glucose
production
DPP-4 Glucose dependent by liver
enzyme  Glucagon from
α cells
(GLP-1)
Inactive Inactive
GLP-1 GIP
*Incretins are also released throughout the day at basal levels.
Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care.
2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441. 16

50. Effects of the Incretin Hormones
GLP-1 GIP
 Is released from L cells in ileum  Is released from K cells in
and colon duodenum
 Stimulates insulin response from  Stimulates insulin response from
β cells in a glucose-dependent β cells in a glucose-dependent
manner manner
 Inhibits gastric emptying  Has minimal effects on gastric
 Reduces food intake and emptying
body weight  Has no significant effects on
 Inhibits glucagon secretion from satiety or body weight
α cells in a glucose-dependent  Does not appear to inhibit
manner glucagon secretion from α cells
 Effect on β-cell turnover in  Effect on β-cell turnover in
preclinical models preclinical models
Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606; Drucker DJ. Diabetes Care. 2003;26:2929–2940;
Farilla L et al. Endocrinology. 2003;144:5149–5158. 14

51. GLP-1 secretion after diet soda ingestion in volunteers
due to stimulation of gut taste receptors by LCS synergizing with
glucose-mediated stimulation of GLP-1 release.

52. .
in volunteers, consumption of diet soda before an oral
glucose challenge potentiates GLP-1 secretion, and insulin
secretion
Translating these results into the clinical setting,
consumption of a LCS in conjunction with a sugar
containing food or drink could lead to more rapid sugar
absorption, as well as increased GLP-1
and potentially altering both gastric emptying and insulin
secretion

53. sucralose given by intragastric infusion
does not stimulates GLP-1 or GIP
release in humans or slow
gastric emptying.
This implies that it may
have no therapeutic benefit in the
dietary management of
diabetes,
other than as a substitute for
carbohydrate
But no GLP-1 increase with sucralose

54. Conclusions
The use of LCS instead of sucrose seems to maintain
and lose weight and to promote long-term dietary
compliance without losing the palatability of the diet
The decrease in energy intakes and the rate of weight
loss that can reasonably be achieved is low, but
meaningful.
There is no clear evidence that LCS augment appetite
or compensation
Indeed, there is emerging evidence that selected NNS
may stimulate the release of satiety hormones like
GLP-1

55. Conclusion II
LCS can help to reduce energy intake, without
compromising taste
LCS give people the opportunity to enjoy a sweet taste
without adding calories to their diet.
LCS, either as ingredients in foods and drinks or as table-
top products, can help people who are seeking to reduce
their energy and sugar intake as part of a healthy and
balanced diet.

56. 56
Thank you very much
for your attention