Sugars and Health: Are we winning
the battle, but losing the war
Sugars and Insulin Resistance
Ian A MacdonaldUniversity of Nottingham Nottingham
Disclosures
AFFILIATION/FINANCIAL INTERESTS
(prior 12 months)
CORPORATE ORGANIZATION
Grants/Research Support: Unilever – Academic lead of UoN strategic
partnership
UK Government/Mars – Project support
Scientific Advisory Board/Consultant: Mars Scientific Advisory Council Waltham Centre for Pet Nutrition
Speakers Bureau: UK Nutrition Society
UK Association for the Study of Obesity
ASN
Stock Shareholder: None
Other UK Government: Dept of Health – Obesity
Review Group, Food Network UK Government: PHE – SACN
Outline
• Insulin action, resistance and basic aspects of dietary carbohydrate
• Fructose – what are the issues? Facts and speculation/opinion
• RCTs of fructose/sucrose supplementation and ectopic fat/insulin resistance
• Is the effect of fructose/sucrose affected by the quantity consumed?
• Does excess energy intake modify the effects of fructose/sucrose?
• Should we be more concerned about dietary glycaemic characteristics than sugars?
• Usually focussed on effects on CHO metabolism - glucose uptake, inhibition EGP, glycogen synthesis, glucose oxidation.
• Also inhibits lipolysis, stimulates TAG clearance and storage in A.T., stimulates Hepatic Lipogenesis.
• Stimulates amino acid uptake, inhibits proteolysis, promotes growth.
• Usually measured as an effect on CHO metabolism
• Need to consider other metabolic effects and whether have differential changes in insulin sensitivity
• (Cardiovascular effects)
Carbohydrate requirements
Have known for nearly 80 years that a minimum CHO intake is needed to achieve good glucose tolerance
Subjects consumed test diets (7.5 - 75% energy as CHO) each for 7 days, then OGTT. Glucose tolerance improved with increasing CHO intake.
Insulin resistance, blood glucose and
disease risk
Metabolic (Insulin resistance) syndrome Microalbuminuria Hypertension Central/abdominal obesity Dyslipidaemia Coronary artery disease Type 2 diabetes HyperinsulinaemiaInsulin resistance is associated with increased all cause mortality from the pre-diabetic state
Arguments that Fructose/Sucrose/HFCS lead to
Insulin Resistance/Metabolic Syndrome
• Increased fructose consumption in US in past 40 years • Adolescents now averaging >70g per day (12% of EI)
• 25% of the population have at least 15% EI from fructose • Nurses Health study and others to identify Potato Chips,
Potatoes/fries, sweets & desserts, SSB as being dietary factors associated with weight gain
• Chronic fructose consumption promotes the MS –
evidence?
• Fructose promotes fatty liver (gives hepatic Insulin resistance) – evidence?
Johnson et al 2013 - Sugar, Uric Acid, and the Etiology of Diabetes and Obesity
‘…For example, rats fed fructose develop fatty liver,
hypertriglyceridemia, and insulin resistance when compared with rats fed isocaloric glucose or starch-enriched diets (4,5). Indeed, hypertriglyceridemia, fatty liver, and type 2 diabetes can be induced in metabolic syndrome–prone rats with caloric restriction provided the diet is high (40%) in sucrose (which contains fructose) (5). A recent epidemiological analysis in
humans also found an association of diabetes prevalence with sugar availability that was independent of total energy intake (13).’
Ref 13 is by Lustig and is an econometric analysis, not a
conventional epidemiological one - The relationship of sugar
to population-level diabetes prevalence: an econometric analysis of repeated cross-sectional data
Some animal evidence of fructose/sucrose leading to insulin resistance, but other studies show impaired
glucose tolerance is due to intestinal effects rather than reduced insulin sensitivity
Sanchez-Lozada et al 2010 - Comparison of free
fructose and glucose to sucrose in the ability to cause fatty liver
• Aim of the study—We studied the chronic effects of a combination of free fructose and glucose relative to sucrose on rat liver.
• Methods—Rats were fed either a combination of 30% fructose and 30% glucose (FG) or 60% sucrose (S). Control rats were fed normal rat chow (C). All rats were pair fed and were followed for 4 months. After killing, blood chemistries and liver tissue were examined.
• Results—Both FG-fed- and S-fed rats developed early features of metabolic syndrome when compared with C. In addition, both diets induced hepatic alterations, including variable increases in hepatic TG accumulation and fatty liver, an increase in uric acid content in the liver, as well as an increase in hepatic levels of monocyte
chemoattractant protein-1 (MCP-1) and TNF-α measured in liver homogenates.
60% of total energy intake from Free Sugars ? Relevance to human nutrition?
Sakamoto et al, 2012 - Ingestion of a moderate high-sucrose diet results in glucose intolerance with reduced liver
glucokinase activity and impaired GLP-1 secretion
• Materials and Methods: C57BL/6J mice received a SUC (38.5% sucrose), a high-starch diet (ST) or a control diet for 5 weeks. Assessed glucose tolerance, insulin sensitivity, and liver glucose metabolism.
• Results: An oral glucose tolerance test (OGTT) showed that plasma glucose levels in the early phase were significantly higher in SUC-fed mice than in ST-fed or control mice, with no change in plasma
insulin levels at any stage. During the OGTT, the accumulation of glycogen in the liver was suppressed in SUC-fed mice.
• However, SUC-fed mice showed a significant improvement in insulin sensitivity during the ITT.
Counter-arguments against concerns
about fructose/sucrose
• Epidemiological literature in this area is mixed.
Meta-analyses of normal consumption levels
of fructose have yielded mixed results related
to obesity.
• Randomized controlled trials at levels even
exceeding normal human consumption have
also been inconclusive related to Fructose,
Sucrose and obesity.
Tappy & Mittendorfer, 2012
• RECENT FINDINGS: Although some studies hint
towards some potential adverse effects of
excessive fructose consumption especially when
combined with excess energy intake, the results
from clinical trials do not support a significant
detrimental effect of fructose on metabolic
health when consumed as part of a
weight-maintaining diet in amounts consistent with the
average-estimated fructose consumption in
Western countries. However, definitive studies
What is the evidence relating to intervention
studies of sugars and insulin resistance/ectopic
fat content?
• Bravo et al 2013 - Consumption of sucrose and high-fructose corn syrup
does not increase liver fat or ectopic fat deposition in muscles
• Heden et al 2014 - Moderate amounts of fructose- or glucose-sweetened beverages do not differentially alter metabolic health in male and female adolescents.
• Aeberli et al 2013 - Moderate Amounts of Fructose Consumption Impair Insulin Sensitivity in Healthy Young Men
• Hokayem et al 2013 - Grape Polyphenols Prevent Fructose-Induced
Oxidative Stress and Insulin Resistance in First-Degree Relatives of Type 2
Diabetic Patients
• Lecoultre et al 2013 - Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans
• Johnston et al 2013 - No difference between fructose and
high-glucose diets on liver triacylglycerol or biochemistry in healthy overweight men.
Lecoultre et al, 2013 - Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans.
(collation of several studies by this group)
• Healthy young subjects, low liver fat content
• Hepatic insulin sensitivity index (HISI), and liver fat (IHCL) measured after 6-7 days on a weight-maintenance diet (control, C) and 6-7 days of overfeeding with
– 1.5, 3, or 4 g fructose/kg/day, – with 3 g glucose/kg/day,
– or with 30% excess energy as saturated fat.
• F3, F4, G3, and fat30% all significantly increased IHCL by 60-100% compared to C
• F3 and F4 significantly decreased HISI by 20 and 19%
• So 100g fructose / day has no effect
• 210 and 280 g fructose / day increases liver fat and produces liver insulin resistance
Metabolic effects of increased fructose
intake
• Intakes up to 100g / day do not appear to affect insulin sensitivity in most studies, although 80g reduced liver sensitivity in one study by approx 15%
• No apparent effects on liver fat of intakes up to the 90th
Centile of US population intakes
• >150g fructose/day reduces index of fasting insulin sensitivity but may need to exceed 250g/day before affecting insulin induced suppression of liver glucose output
• Is the effect of fructose/sucrose related to energy balance?
Johnston et al 2013
Effects of fructose/glucose on liver and muscle fat content –
1H MRS and hyperinsulinaemic clamp in a sub-group
32 overweight men with large waist (>94cm) – studied for two separate 2wk periods
1st energy balance - 75% from food (all supplied)
- 25% from glucose / fructose powder added to water 2nd overfed - 100% from food (own habitual intake)
Subjects – overweight, large waist,
otherwise healthy men
Fructose n=15 Glucose n=17 p Age 35±11 33±9 0.60 Weight (kg) 96.8±7.4 93.9±8.7 0.32 BMI (kg/m2) 30.0±1.4 28.9±1.7 0.07 Body fat (%) 34.5±4.6 33.9±4.2 0.70 Waist (cm) 103.8±4.9 103.3±5.2 0.77
Results
isocaloric hypercaloric weight (kg) 90 95 100 * * isocaloric hypercaloric HTGC (%) 0 5 10 15 * *Body weight Liver fat
F G F G F G F G
At energy balance, Fructose and Glucose had no effect on liver fat content.
With overfeeding, Fructose and Glucose both increased liver fat content.
Serum TAG
isocaloric hypercaloric Triglyceride (mmol/L) 0.0 0.5 1.0 1.5 2.0 * * F G F GNo effect on BP or SNS activity with either sugar in either condition
Fructose during ‘isocaloric’ feeding was associated with small increases in uric acid and fasting insulin resistance (HOMA-IR) but neither sugar affected these or any other serum variables (except TAG) during overfeeding
Fructose, n=6 Glucose, n=6 Glucose disposal (mg/kg/min) 4.50±1.84 5.01±1.59 Fasting EGP (mg/kg/min) 2.07±1.31 1.93±1.49 End of clamp EGP (mg/kg/min) 1.02±0.68 1.17±0.73
Baseline
Change from Baseline after isocaloric feeding
All, n=12 Fructose, n=6 Glucose, n=6
Glucose disposal (mg/kg/min) -0.49±1.2 -0.29±1.5 -0.68±0.83 Fasting EGP (mg/kg/min) -0.04±1.82 -0.35±1.73 0.27±2.01 End of clamp EGP (mg/kg/min) 0.19±1.38 -0.11±1.36 0.50±1.47
Change from Baseline after overfeeding
All, n=12 Fructose, n=6 Glucose, n=6 Glucose disposal (mg/kg/min) -0.51±1.2 -0.29±0.84 -0.73±1.51 Fasting EGP (mg/kg/min) 0.24±1.62 0.32±2.27 0.17±0.81 End of clamp EGP (mg/kg/min) 0.11±1.03 -0.20±1.01 0.41±1.05
No significant change in insulin sensitivity, although a trend for a small reduction, more so for glucose than fructose
Conclusions
• Fructose / sucrose can affect insulin sensitivity but only with high intakes - >100g F / d
• Overeating is associated with increased liver and muscle fat, but the effect is similar for Fructose and Glucose
• Short term overfeeding with Fructose or Glucose does not lead to major changes in liver or whole body
insulin sensitivity. More studies are needed with larger subject numbers to delineate this further.
• Is the focus on sugars mis-directed? What about GI/GL?
Impact of low v. high GI/GL diets on liver
glycogen and lipid (MRS) in healthy young men
(Bawden et al, unpublished)
High GI has expected effect on liver glycogen but also increases liver lipid Not known if it affects insulin resistance
Misconceptions about fructose-containing sugars and their role in the obesity epidemic.
van Buul, Tappy & Brouns, 2014 - Nutrition Research Reviews
…. fructose, as commonly consumed in mixed carbohydrate sources,
does not exert specific metabolic effects that can account for an increase in body weight. Consequently, public health
recommendations and policies aiming at reducing fructose
consumption only, without additional diet and lifestyle targets, would be disputable and impractical. Although the available evidence
indicates that the consumption of sugar-sweetened beverages is
associated with body-weight gain, and it may be that fructose is
among the main constituents of these beverages, energy
overconsumption is much more important to consider in terms of the obesity epidemic.
The possibility that glycaemic index is more influential than fructose / sucrose on ectopic fat and possibly insulin resistance
High heterogeneity
N= 2
? Justification for a meta-analysis?
Te Morenga et al, (2013)
for WHO report
Bravo et al 2013
Consumption of sucrose and high-fructose corn syrup does not increase liver fat or ectopic fat deposition in muscles
• For 10 weeks, 64 individuals (mean age, 42.16 ± 11.66 years) consumed low-fat milk sweetened with either high-fructose corn syrup (HFCS) or sucrose; the added sugar matched
consumption levels of fructose in the 25th, 50th, and 90th percentiles of the population. The fat content of the liver was measured with unenhanced computed tomography imaging, and the fat content of muscle was assessed with magnetic resonance imaging.
• When the 6 HFCS and sucrose groups were averaged, there was no change over the course of 10 weeks in the fat content of the liver, vastus lateralis muscle or gluteus maximus
The highest intakes associated with weight gain
But no change in ectopic fat content of muscle or liver
Heden et al 2014 - Moderate amounts of fructose- or glucose-sweetened beverages do not differentially alter metabolic health in
male and female adolescents.
• 40 male and female adolescents completed two 2-wk trials that included 1) an HF trial in which they
consumed 710 mL of a sugar-sweetened beverage/d (equivalent to 50 g fructose/d and 15 g glucose/d) for 2 wk and 2) an HG trial in which they consumed 710 mL of a sugar-sweetened beverage/d (equivalent to 50 g glucose/d and 15 g fructose/d) for 2 wk in addition to their normal ad libitum diet.
• Body weight, QUICKI (whole-body insulin sensitivity), HOMA-IR (hepatic insulin resistance), and fasting lipids, cholesterol, glucose, lactate, and insulin secretion or clearance were not different between trials.
Aeberli et al 2013 - Moderate Amounts of Fructose Consumption Impair Insulin Sensitivity in Healthy Young Men
Healthy young men, low BMI, low reported energy intakes – 1800-2300 kcal/day. No difference in systemic insulin sensitivity but small reduction in hepatic insulin
Low insulin infusion rates to give incomplete suppression of EGP
No change in whole body glucose disposal but reduced suppression of EGP with high Fructose intake
Hokayem et al 2013 - Grape Polyphenols Prevent Fructose-Induced Oxidative Stress and Insulin Resistance in First-Degree
Relatives of Type 2 Diabetic Patients
• Overweight, large waist men and women with family history of T2DM
• 8 weeks of placebo or grape polyphenol consumption then a further week with 3g fructose/kgFFM = >150g fructose per day
• Two stage insulin infusion glucose clamp – liver then whole body insulin resistance
